The bisphosphonates (BPs) are well established as the treatments of choice for disorders of excessive bone resorption, including Paget's disease of bone, myeloma and bone metastases, and osteoporosis. There is considerable new knowledge about how BPs work. Their classical pharmacological effects appear to result from two key properties: their affinity for bone mineral and their inhibitory effects on osteoclasts. Mineral binding affinities differ among the clinically used BPs and may influence their differential distribution within bone, their biological potency, and their duration of action. The inhibitory effects of the nitrogen-containing BPs (including alendronate, risedronate, ibandronate, and zoledronate) on osteoclasts appear to result from their inhibition of farnesyl pyrophosphate synthase (FPPS), a key branch-point enzyme in the mevalonate pathway. FPPS generates isoprenoid lipids used for the posttranslational modification of small GTP-binding proteins essential for osteoclast function. Effects on other cellular pathways, such as preventing apoptosis in osteocytes, are emerging as other potentially important mechanisms of action. As a class, BPs share several common properties. However, as with other classes of drugs, there are obvious chemical, biochemical, and pharmacological differences among the various individual BPs. Each BP has a unique profile that may help to explain potential important clinical differences among the BPs, in terms of speed of onset of fracture reduction, antifracture efficacy at different skeletal sites, and the degree and duration of suppression of bone turnover. As we approach the 40th anniversary of the discovery of their biological effects, there remain further opportunities for using their properties for medical purposes.

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Clinical risk factors are associated with increased probability of fracture in postmenopausal women. We sought to compare prediction models using self-reported clinical risk factors, excluding bone-mineral density (BMD), to predict incident fracture among postmenopausal women. The GLOW study enrolled women aged ≥55 years were seen at 723 primary care practices in 10 countries. The population comprised 19,586 women aged ≥60 years who were not receiving anti-osteoporosis medication and were followed annually for 2 years. Self-administered questionnaires were used to collect data on characteristics, fracture risk factors, previous fractures, and health status. The main outcome measure compares the c index for models using the WHO Fracture Risk (FRAX), the Garvan Fracture Risk Calculator (FRC), and a simple model using age and prior fracture. Over 2 years, 880 women reported incident fractures including 69 hip fractures, 468 “major fractures” (as defined by FRAX) and 583 “osteoporotic fractures” (as defined by FRC). Using baseline clinical risk factors, both FRAX and FRC showed moderate ability to correctly order hip fracture times (c index for hip fracture: 0.78 and 0.76, respectively). C indices for “major” and “osteoporotic” fractures showed lower values, at 0.61 and 0.64. Neither algorithm was better than the model based on age+fracture history alone (c index for hip fracture: 0.78). In conclusion, estimation of fracture risk in an international primary care population of postmenopausal women can be made using clinical risk factors alone, without BMD. However, more sophisticated models incorporating multiple clinical risk factors including falls were not superior to more parsimonious models in predicting future fracture in this population.

This article provides the first comprehensive taxonomy of rare metabolic skeletal diseases based on deranged metabolic activity. This classification will help in the development of common and shared diagnostic and therapeutic pathways for these patients and also in the creation of international registries of rare skeletal diseases, the first step for the development of genetic tests based on next generation sequencing and for performing large intervention trials to assess efficacy of orphan drugs.

The data suggest that there may be regional differences in the proportion of major fractures that are hip fractures in postmenopausal women. In contrast, the regional and age-related variations in the proportion of fractures that are major fractures appear to be modest. However, because of the limited number of fractures in our sample, further studies are necessary to confirm these findings.